Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance.

Authors:
Ben C Creelan
Ben C Creelan
H. Lee Moffitt Cancer Center and Research Institute
United States
Jhanelle E Gray
Jhanelle E Gray
H. Lee Moffitt Cancer Center and Research Institute
Tampa | United States
Tawee Tanvetyanon
Tawee Tanvetyanon
H. Lee Moffitt Cancer Center and Research Institute
Tampa | United States
Alberto A Chiappori
Alberto A Chiappori
H. Lee Moffitt Cancer Center and Research Institute
Takeshi Yoshida
Takeshi Yoshida
Tokyo Medical and Dental University
Japan
Michael J Schell
Michael J Schell
H. Lee Moffitt Cancer Center and Research Institute
Tampa | United States
Scott J Antonia
Scott J Antonia
Medical College of Georgia
United States
Eric B Haura
Eric B Haura
H. Lee Moffitt Cancer Center and Research Institute
Tampa | United States

Br J Cancer 2019 Apr 18;120(8):791-796. Epub 2019 Mar 18.

Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA.

Background: Bypass activation of Src family kinases can confer resistance to EGFR tyrosine kinase inhibitors (TKIs) based on preclinical models. We prospectively assessed the safety and clinical activity of dasatinib and afatinib in combination for patients with resistant EGFR-mutant lung cancer.

Methods: An open-label, dose-escalation phase 1/2 trial (NCT01999985) with 2-stage expansion was conducted with 25 lung cancer patients. Dose expansion required activating EGFR mutations and progression following prior EGFR TKI.

Results: Patients were 72% Caucasian and received median of 2 prior lines of therapy. Maximum-tolerated dose was 30 mg afatinib with 100 mg dasatinib. New or increased pleural effusions were observed in 56% of patients. No radiologic responses were observed, although several EGFR-mutant TKI-resistant patients (26%) had prolonged stable disease over 6 months. The combination reduced the EGFR mutation and T790M variant allele frequency in cell-free DNA (p < .05). Nonetheless, the threshold for futility was met, based on 6-month progression-free survival. For EGFR TKI-resistant patients, median progression-free survival was 3.7 months (95% confidence interval (CI), 2.3-5.0) and overall survival was 14.7 months (95% CI, 8.5-20.9).

Conclusions: The combination had a manageable toxicity profile and in vivo T790M modulation, but no objective clinical responses were observed.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-019-0428-3DOI Listing
April 2019

Publication Analysis

Top Keywords

lung cancer
8
tyrosine kinase
8
patients
5
activating egfr
4
egfr mutations
4
mutations progression
4
median prior
4
required activating
4
dose expansion
4
expansion required
4
progression prior
4
prior egfr
4
72% caucasian
4
caucasian received
4
patients 72%
4
tkiresults patients
4
patients dose
4
egfr tkiresults
4
received median
4
cancer patients
4

References

(Supplied by CrossRef)
Article in Clin. Cancer Res.
LP Stabile et al.
Clin. Cancer Res. 2013
Article in Clin. Cancer Res.
T Yoshida et al.
Clin. Cancer Res. 2014
Article in Mol. Cancer Ther.
S Watanabe et al.
Mol. Cancer Ther. 2017
Article in J. Clin. Oncol.
EB Haura et al.
J. Clin. Oncol. 2010
Article in Cancer Res.
ML Sos et al.
Cancer Res. 2009
Article in Cancer Res.
R Kanda et al.
Cancer Res. 2013
Article in Sci. Rep.
TF Lee et al.
Sci. Rep. 2018
Article in J. Clin. Investig.
KS Park et al.
J. Clin. Investig. 2014
Article in Oncotarget
H Zhang et al.
Oncotarget 2017
Article in Am. Soc. Clin. Oncol.
PD Fan et al.
Am. Soc. Clin. Oncol. 2017
Article in Proc. Natl. Acad. Sci. USA
PD Fan et al.
Proc. Natl. Acad. Sci. USA 2018

Similar Publications